WO1999057121A1

WO1999057121A1 - Carbapenem derivatives, utilization thereof and intermediate compounds of the same

Info

Publication number: WO1999057121A1
Application number: PCT/JP1999/002301
Authority: WO
Inventors: Hiroshi Matsui
Original assignee: Kyoto Pharmaceutical Industries, Ltd.
Priority date: 1998-05-01
Filing date: 1999-04-28
Publication date: 1999-11-11
Also published as: ID27081A; BR9910098A; EP1078927A4; CA2330641A1; CN1307578A; CZ20003954A3; CZ292623B6; NO20005480L; EP1078927A1; KR100589030B1; PL343728A1; TW528750B; US6410525B1; SK16382000A3; DE69932927D1; TR200003199T2; AU760386B2; EP1078927B1; BG105004A; RU2222540C2

Abstract

Carbapenem compounds represented by general formula (I) wherein R1 represents a modifying group hydrolyzable in vivo; R?2 and R3¿ may be the same or different and each represents lower alkyl; and R represents a group represented by formula (B) or formula (C) (wherein R?4 and R5¿ may be the same or different and each represents hydrogen or lower alkyl; and R6 represents C¿1-10? alkyl). When administered orally, the compounds (I) are excellent in the absorbability via the digestive tract and exhibit sufficient antibacterial effects over a broad scope of bacterial species. Thus, they are highly useful as preventives/remedies for infectious diseases, in particular, microbisms.

Description

Specification

Technical Field

The present invention relates to a novel active compound useful as an agent for preventing or treating bacterial infections. More specifically, a novel potent antibacterial compound having sufficient antibacterial properties and oral absorbability, an oral antibacterial agent containing the compound as an active ingredient, and an intermediate for the production of the potent antifungal compound. Body compounds.

Background art

To date, many compounds having a carbane skeleton have been found as therapeutic agents for infectious diseases, and some of these compounds having excellent antibacterial activity have been put to practical use or Development is underway. For example, the formula (A)

The compound represented by is already in practical use and is being used clinically. This compound has a broad antibacterial spectrum and strong antibacterial activity, and also overcomes the instability of renal dehydrobeptidase, which was a drawback of conventional compound. It has an excellent feature that it can be administered alone without using a stabilizer in combination.

However, these potent compounds are poorly absorbed from the digestive tract and are only administered clinically as injections. Oral preparations are easier and easier to administer than injections, and their clinical utility is extremely high. Therefore, there is a strong demand for the development of a compound for oral administration which has a strong antibacterial activity and a broad antibacterial spectrum, and has an excellent gastrointestinal absorption property. Disclosure of the invention

An object of the present invention is to provide a potent lubebenem compound having excellent antibacterial properties and absorption from the digestive tract. Another object of the present invention is to provide a use of the compound. Still another object of the present invention is to provide an intermediate suitable for the production of the compound.

The present inventors have conducted intensive studies to achieve the above object, and as a result, the novel potash compound represented by the following general formula (I) has excellent gastrointestinal absorption properties, and Have found that these compounds have sufficiently strong antibacterial properties and are extremely useful as antibacterial agents for oral use. Further, they have found novel intermediate compounds used for the production of the compounds, and have completed the present invention. Was. That is, the present invention is an invention described in the following (1) to (10).

(1) General formula (I)

[Wherein, R ¹ represents a modifying group that is hydrolyzed in vivo, R ^z and R ³ may be the same or different and each represents a lower alkyl group, and R represents a compound of the formula (B)

Or a group represented by the formula (C) CO

(Wherein R ⁴ and R ⁵ may be the same or different and each represents a hydrogen atom or a lower alkyl group, and R ⁶ represents an alkyl group having 1 to 10 carbon atoms) A compound represented by the formula:

(2) The compound according to (1), wherein R ² and R ³ may be the same or different and are each a lower alkyl group.

(3) The compound according to (1), wherein R ¹ is a bivaloyloxymethyl group.

(4) The compound according to (1), wherein R ¹ is a 1-cyclohexyloxycarbonyloxetyl group.

(5) The compound according to (1), wherein R ¹ is a 1-ethoxycarbonylquinethyl group.

(6) Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5-N, N-dimethylaminocarbone-l- (5-Methyl-2 —Okifu

1,3-Dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-1-ylthio} -6-[(1R) -1-hydrodroxystyl] -1-methylcarbapene-2-em-3 Carboxylates,

1-cyclohexyloxycarbonyloxyshetyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5 -N, N-dimethylaminocarbone 1- (5 — Methyl-1,2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidine-1,3-ylthio} — 6 — [(1R) —1—Hydroxitytyl] 1—methylcarba Pen 1 2—Emu 3—Carboquinate,

1 1-Ethoxycarbonyloxetyl (1R, 5S, 6S) -2-({3S, 5S)-[5-N, N-dimethylaminocarbone- 1- (5-methyl-1 2-oxo-1, 3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-1-3-ylthio} -1 6-[(1R) -11-hydroxyl] ethyl-1-methylca Luba's pen-one 2-emmu 3-carboxylate,

Bivaloyloxymethyl (1 R, 5 S. 6 S)-2-C (3 S. 5 S)-(5 -N, N-dimethylaminocarbone 1-acetyloxymethylquinquincal Bonyl) pyrrolidine-l-ylthio] _ 6- [(1R) -l-hydroxyxethyl] 1-methylcarbapene-12-em-13-carboxylate;

Bivaloyloxymethyl (1R, 5S.6S)-2-C (3S, 5S)-(5-N, N-dimethylaminocarboxyl 1-propionyloxymethyloquin carbonyl) Pyrrolidine-1-3-ylthio] 1-6 — [(1R) -1—hydroxyethyl] -1-methylcarbapene-12-ammon-3-carboxylate,

Pivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-Dimethylaminocarbonyl 1-Ilib thousand riloxymethylo Quincarbonyl) pyrrolidine-1-3-ylthio] -1 6-C (1R) _1-hydroxyl] 1-1-methylcarbapene-2-emum 3-carboxylate,

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-dimethylaminocarboxyl 1-bivaloyloxymethyloxycarbonyl) ) Pyrrolidine-13-ylthio] -16-[(1R) -1-1-hydroxyl] -1-methylcarbapene-2-em-13-carboxylate,

Viva α-yloxymethyl (1 R. 5 S. 6 S)-2-C (3 S. 5 S)-(51-Ν, Ν-dimethylaminocarboxyl 1-isovaleryl-loquinmethyloxycarbonyl) Pyrrolidine-1-3-ylthio] -1 6-[(1R) -1-1-hydroxyl] 1-1-1-methylcarbapene-2-em-13-carboxylate,

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S. 5 S)-(5 -Ν, Ν-dimethylaminocarbonyl 1-tert-butyl-cetyloxymethyloxy Carbonyl) pyrrolidine-l-ylthio]-6- [(1R)-1 -hydroxyxetyl] -l-methylcarbapene-2 -em-3 -carboxylate,

1-cyclohexyloxycarbonyloxyshetyl (1R, 5S, 6S) -2—C (3S, 5S) one (5—N.N—dimethylaminocarbonyl-1-1-isobu Tyrylloquinmethyloxycarbonyl) pyrrolidine-l-ylthio] -l6-((1R) -l-hydroxyethyl) -l-methylcarbapene-l-emu- 3-carboxylate, and

1-ethoxycarbonylquinethyl (1 R, 5 S, 6 S)-2-C (3 S. 5 S)-(5 -N, N-dimethylaminocarbone 1-bivaloyloxymethyl (1) -pyrrolidine-1-3-ylthio] -1 6-[(1R) -1-1-hydroxyxyl] -11-methylcarbapene-2-emu-3-carboxylate Power compounds.

(7) An antibacterial agent comprising the active compound represented by the general formula (I) described in (1) as an active ingredient.

(8) The antibacterial agent according to (7), which is for oral administration.

(9) General formula (II)

[Wherein R ² and R ³ may be the same or different and each represents a lower alkyl group, R ⁷ represents a hydrogen atom or a carboxyl-protecting group, and R represents a group represented by the formula (B)

Or a group represented by the formula (C) (C)

(Wherein, R ⁴ and R ⁵ may be the same or different and each represents a hydrogen atom or a lower alkyl group, and R ⁶ represents an alkyl group having 1 to! 0 carbon atoms) A compound represented by the formula: or a salt thereof.

(1 0) p—Nitrobenzil (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-

[5-N, N-Dimethylaminocarbonyl-2- (5-methyl-12-oxo-I, 3-dioxolen-41-yl) methyloxycarbonyl] pyrrolidine-1-3-ylthio} — 6— [(1 R) 1-1-Droxitytil] 1-1-methylcarbapene 1-2 emu 3-Carboquinate,

(1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5-N, N-dimethylaminocarbone-l- (5-methyl- 1-2-oxo2, 3-dioxolene 4) — (Yl) methyloxycarbonyl] pyrrolidine-1-ylthio} -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-enecarboxylic acid, p-nitro Benzyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5-N, N-dimethylaminocarbone 1-loop ^ pionyloxymethyloxycarbonyl) Pyrrolidine-1-3-ylthio] 1-6—C (1R) —1—hydroxyxethyl] 1-1-methylcarbapene-12-em-1-3-carboxylate,

p-Nitrobenzyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5-N, N-Dimethylaminocarboyl 1-isobutyryloxymethyloxy Carbonyl) pyrrolidine-1-3-ylthio] 1-6 — [(1R) -1—Hydroxitytyl] 1-1-Methylcarbapene1-2-em-13-carboxylate,

(1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5-N, N-dimethylaminocarbonyl-1 1-propionyloxymethyloquincarbonyl) pyrrolidine-1

3- (ylthio) -1-6-((1R) -1-hydroxyxethyl) -1-1-methylcarbapene-2-em-3-carboxylic acid, and (1R, 5S, 6S) 1-2-[(3S, 5S)-(5-N, N-dimethylaminocarbone-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-1-3-ylthio] 1-6 — [(1R) —1—Hydroxitytyl] 1—1 Methylcarbapene 1—2—Emmou-3-carboxylic acid selected from the group consisting of carboxylic acids described in (9) or a salt thereof (particularly , Sodium salt).

Detailed description of the invention

Hereinafter, each definition used in the present specification will be described.

The “modifying group that is hydrolyzed in vivo” for R ¹ is preferably one that is hydrolyzed in the intestinal tract or blood, and includes, for example, an aryl group which may have a substituent (for example, Phenyl group, tolyl group, xylyl group, indanyl group, etc.), 1-alkynylquinoylalkyl group, 1-alkoxycarbonyloquinalkyl group, furidyl group, and 5-methyl-2-oxo-1,3-dioxolene 1-4-methyl group and the like. Of these, an alkanoloxyalkyl group, an alkoxycarbonyloxyalkyl group and a 5-methyl-2-oxo-1,3-dioxolen-14-ylmethyl group are preferred.

The "aryl group optionally having substituent (s)" is preferably an aryl group which may be unsubstituted or optionally substituted by 1 to 3 substituents, and the substituents may be the same or different. Is also good. Specific examples of the substituent include an alkyl group having 1 to 4 carbon atoms such as a methyl group and an ethyl group.

The number of carbon atoms in the alkynyl moiety in the "1 alkynyloxyalkyl group" is preferably 2 to 10, more preferably 2 to 7, and may be linear, branched, or cyclic. The number of carbon atoms in the alkyl moiety is preferably 1 to 3, more preferably 1 or 2.

Examples of the “1 alkanoyloxyalkyl group” include, for example, an acetomethyl group, a propionyloxymethyl group, an n-butyryloxymethyl group, an isobutyryloxymethyl group, a bivaloyloxymethyl group, and an n-valeryloxymethyl group Group, 2-methylbutyryloxymethyl group, isovaleryloxymethyl group, n-hexano Yloxymethyl group, 3-methylvaleryloxymethyl group, neohexanoylquinine methyl group, 2-methylhexanoyloxymethyl methyl group, 2,2-dimethylvaleryloxymethyl group, neohepnoyloxymethyl group, cyclohexanecarbonyloxymethyl group , Cyclohexylacetoxymethyl group, 1-acetoxityl group, 1-propionyloxyxetyl group, I—n-butyryloxyxetyl group, 1 1-butyryloxicetyl group, 1—II-valery Examples include a luxechyl group, a 1-vivayloxyxetyl group, a 1-isovaleryloxextyl group, a 1-n-hexanoyloxextyl group, and a 1-cyclohexanecarbonyloxextyl group.

The number of carbon atoms in the alkoxy moiety in the “1-alkoxycarbonylalkyl group” is preferably from 1 to 10, more preferably from 1 to 7, and may be any of linear, branched or cyclic. And the number of carbon atoms in the alkyl moiety is preferably 1 to 3, more preferably 1 or 2.

Examples of the “1-alkoxycarbonyloxyalkyl group” include, for example, a 1-methoxycarbonylcarbonyloxyl group, an 11-ethoxycarbonyloxylethyl group, an 11-n-propoxycarbonyloxyloxyl group, 1 1-Isopropoxycarboxyloxyethyl, 1—n-butoxycarbonyloxyquinethyl, 1—sec—butoxycarbonyloxyethyl, 1—t Butoxycarbonyloxyquinethyl, 1 1 A pentyloxycarbonyloxyshetyl group and a 1-cycloα-hexyloxy force ruponyloxicetyl group.

The “lower alkyl group” in R ² , R ³ , R * and R ⁵ means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, Propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, neohexyl, etc. Is mentioned. Of these, a methyl group, an ethyl group, a propyl group and a butyl group are preferred.

“Alkyl group” in R ^fi refers to a linear or branched chain with 1 to 10 carbon atoms. Or a cyclic alkyl group, such as methyl, ethyl, propyl, isobutyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl Group, t-pentyl group, cyclopentyl group, hexyl group, isohexyl group, neohexyl group, sec-hexyl group, t-hexyl group, cyclohexyl group, heptyl group, isoheptyl group, neo Examples include a heptyl group, sec-heptyl group, t-heptyl group, octyl group, isooctyl group, neooctyl group, sec-octyl group, t-octyl group and the like.

Examples of the “protecting group for the carboxyl group” in R ⁷ include a t-butyl group, a neopentyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a diphenyloxymethyl group, a p-nitrophenyl group , Methoxymethyl group, ethoxyquinmethyl group, benzyloquinmethyl group, methylthiomethyl group, trityl group, 2,2,2-trichloromethyl group, trimethylnyl group, diphenylmethoxybenzenesulfonylmethyl group, dimethylaminoethyl group, etc. Is mentioned. Of these, p-nitrobenzyl, p-methoxybenzyl and diphenylmethyl are preferred.

When the carbane compound (II) has a carboxyl group (when R ⁷ is a hydrogen atom), a salt can be formed at the carboxyl group. Examples of the salt in the carboxyl group include an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, etc.), an organic base salt (eg, triethylamine, etc.) Salt, dicyclohexylamine salt, pyridine salt, etc.).

Specific examples of preferred compounds of the compound (I) of the present invention are as follows.

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5-N, N-Dimethylaminocarbo-nitro 1-1 (5-Methyl-1-2-oxo 1-, 3-Dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-1-ylthio} 1-6 — [(1R) 1-1-Hydroxityl] —1-Methylcarbapene-1 2 —Arm 3—Carboquinate,

1-cyclohexyloxycarbonyloquinethyl (1 R, 5 S, 6 S)-2— {(3 S, 5 S)-[5 -N, N-dimethylaminocarbone 1- ( 5-Methyl-2-yl 1,2-dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-3-ylthio} — 6 — [(1R) —1-Hydroxitytyl] 1-1-methylcarba Pen one-two-one three-carboxylate,

1-Ethoxycarbonylcarbonylquinethyl (1 R, 5 S, 6 S)-2-{(3 S. 5 S) 1-[5 -N, N-dimethylaminocarbone 1- (5-methyl- 2-oxo-1, 3-dioxolen-1-yl) methyloxycarbonyl] pyrrolidin-1-3-ylthio-1-6-[(1R) 1-1-hydroxyloxetyl] ― 1 —methylcarbapene 3-carboxylate,

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5 -N, N-Jethylaminocarbonyl-1- 1-(5-methyl-1- 2-oxo 1-Dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-1-ylthio} — 6 — [(1R) —1-Hydroxyethyl] 1-1-methylcarbapene-1 2-emu3 —Carboxylate,

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5-N-Ethyl-1-N-Methylaminocarbone-2 1- (5-Methyl-2- Oxo-1, 3-Dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-1 3-ylthio} — 6— [(1 R) — 1-hydroxyxethyl] 1 1-methylcarbabenzene 1 2 3-carboxylate,

Bivaloyloquinmethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-Dimethylaminocarbone 1-acetyloxymethyl methylquincal Bonyl) pyrrolidine-l-ylthio] — 6— C (1 R) — 1-hydrodroquinethyl] 1-methylcarbapene 2-em-1 3-carboquinate,

Bivaloyloxymethyl (1R, 5S, 6S) -2-((3S.5S)-(5-N, N-dimethylaminocarboxyl 1-propionyloxymethyloxy) Carbonyl) pyrrolidine-1-3-ylthio] — 6 — [(1R) —1-hydroxylethyl) 1 1 1-methylcarbapene 12-ammon-3-carboxylate,

Bivaloyloxymethyl (1R, 5S, 6S) -2-C (3S, 5S)-(5-N, N-dimethylaminocarboxyl 1-isobutyryloxymethyloxycarbonyl) Pyrrolidine-1-3-ylthio] — 6 — [(1R) -1—Hydroxyethyl] 1-1—Methylcarbapene-2-Em-3-3-carboxylate,

Bibacoyl oxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N.N—Dimethylaminocarbone 1 — Vivaloyloquinoxymethyl carbonyl) Pyrrolidine-1-3-ylthio] -1 6-[(1R) -1 -Hydroxyshethyl] 1-1-1 Methylcarbapene-12-emou 3-carboxylate,

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-dimethylaminocarbonyl 1-isovaleryloxymethyloxycarbonyl) Pyrrolidine-1-3-ylthio] — 6— ((1R) — 1-hydroxylethyl) — 1-methylcarbapene 2-hem — 3-carboquinate,

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-dimethylaminocarbonyl 1 1-tert-butylacetyloquine methyloxy Carbonyl) pyrrolidin-13-ylthio] -16-[(1R) -1 -hydroxyl] -1-1-methylcarbapene-2-em-1-3-carboquinate,

1-cyclohexyloxycarbonyloxyshetyl (1R, 5S, 6S) -2-[(3S, 5S) 1- (5-N, N-dimethylaminocarbocarbonyl 1-isobutyryl (Xymethyloxycarbonyl) pyrrolidin-1-ylthio] — 6— ((1R) — 1-hydroxyxyl) 1-methylcarbapene-12-emou 3-carboxylate,

1 1-Ethoxycarbonylcarbonylsulfonyl (1R, 5S, 6S) -2-C (3S, 5S)-(5-N, N-dimethylaminocarbonyl-1 1-Bivaloyloximetilo Quincarbonyl) pyrrolidin-13-ylthio] -16-C (1R) -11-hydroxyl) -1-1-methylcarbapene-2-em-13-carboxylate, Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 —N-ethyl-N-methylaminocarbonyl— 1-propionyloxymethyloxycarbonyl) Pyrrolidine-1-3-ylthio] — 6— ((1R) — 1 —Hydroxyshetyl) 1-methylcarbaben-12-em—3-carboquinate and bivaloyoxymethyl (1R, 5 S, 6 S)-2-C (3 S, 5 S) — (5 -N, N-Jethylaminocarbocarbonyl 1-propionyloxymethyloquin carbonyl) pyrrolidine-1 3-ylthio] 1 6— [(1R) -1-1-hydroxyethyl] -1-methylcarbapene-12-ammon-3-carboquinate and the like. Specific examples of preferable compounds of the compound (II) of the present invention are as follows.

p-Nitrobenzyl (1 R, 5 S, 6 S) — 2 — {(3 S, 5 S) — C 5 -N, N—dimethylaminocarbonyl 2- 1- (5-methyl-2-oxo I 1.3-Dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-1-3-ylthio} — 6 — [(1R) —1—Hyd π-xicetyl] —1-Methylcarbapene—2-Emu3 —Carboquin rate,

(1 R, 5 S, 6 S)-2-{(3 S, 5 S) — [5— N, N-dimethylaminocarbone 1 1 (5—methyl-1 2-oxo-1, 3-dioxolen-1 4-yl) methyloxycarbonyl] pyrrolidine-3-3-ylthio} -6-[(1R) -1-1-hydroxyxetyl] 1-1-methylcarbaben-2-em-1-3-sodium sodium rubonate,

p-Nitrobenzil (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5-N, N-dimethylaminocarbonyl- 1-p α-pionyloquinine methyloxy (Carbonyl) pyrrolidine-l-ylthio]-6-[(1R)-1-Hydroxitytyl] 1-1-Methylcarbapene-2-hem-3-carboxylate,

ρ—Nitrobenzil (1 R, 5 S. 6 S) — 2— [(3 S, 5 S)-(5 -N, N-dimethylaminocarbo-2-yl 1-isobutyryloxymethylo Xyxalbonyl) pyrrolidine-1-ylthio] — 6— ((1R) — 1 — hydroquinethyl 1-methylcarbapene 2-em- 3-carboquinate,

(1 R, 5 S. 6 S)-2-C (3 S, 5 S) — (5—N, N—dimethylaminocarbocarbonyl 1 —propionylloquinemethyloxycarbonyl) pyrrolidine

3-ylthio] -1-6-((1R) -1-hydroxyl-shethyl) -1-1-methylcarbapene-2-em-3-potassium sodium rubonate, and

(1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-dimethylaminocarbonyl-1 -isobutyryloxymethyloquincarbonyl) pyrrolidine

3-ylthio] — 6— [(1 R) — 1-hydroxyxyl] — 1-methylcarbapene 2- 2-emudium 3-carboxylate

The potassium hydroxide compound (I) and the potassium hydroxide compound (II) which is an intermediate compound thereof can be produced by any of the following production methods 1 to 5.

Wherein R ¹ , R ² , R ³ and R are as defined above, X is a halogen atom such as chlorine, bromine or iodine, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy and butyl. It represents a leaving group such as an arylsulfonyloxy group such as a sulfonyloxy group and a phenylsulfonyloxy group such as phenylsulfonyloxy and tolylsulfonyloxy. ]

Compound (I) is a solvent that does not inhibit the reaction (eg, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N.N-dimethylformamide, N, N —Dimethylacetamide, dimethylsulfoxide, or the like, or a mixture thereof), dissolving compound (IIa) in the presence of a base, in an amount of about 1 to 5 moles, preferably about 1 to 2 moles, It is obtained by reacting with the compound (III).

The base used is not particularly limited, but is preferably an inorganic base such as sodium bicarbonate or carbonated carbonate, or an organic base such as triethylamine, disopropylpyrethylamine, pyridine or the like. Can be

The reaction temperature is not particularly limited, is preferably carried out at a relatively low temperature to suppress side reactions, usually one 3 0 to 4 0 ^e C, it is preferably carried out in one 1 0~ 1 0 ° C. The reaction time varies mainly depending on the reaction temperature, the type of the reaction reagent, and the like, but is usually 30 minutes to 10 hours.

The compound (IIa) may be, if necessary, a reactive derivative thereof (for example, an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt, a triethylamine salt, and a dicyclohexaneamine salt). , Pyridine salts, etc.) and react with the compound (III).

[Wherein, R ′, R ² , R ³ and R have the same meanings as described above, and Y is chlorine, imidaboyl 1-yl, ρ-ditrophenyloxy and 2-phenylacetonitrile. Represents a leaving group such as a 2-ylaminoquinone group. ]

Compound (I) is a solvent that does not inhibit the reaction (eg, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, Ν, Ν-dimethylformamide, Ν, Ν —Dimethylacetamide, dimethylsulfoxide, etc., or a mixture thereof), and reacting the compound (〗 V) with about 1 to 5 moles, preferably about 1 to 2 moles, of the compound (V). It is obtained by doing. Compound (IV) is reacted with carboxylic acid and compound (III) described in JP-A-60-233076 in the same manner as in Production Method 1. It can be obtained by:

This reaction can also be performed in the presence of a base. The base used is not particularly limited, but is preferably an inorganic salt such as sodium hydrogencarbonate or potassium carbonate or an organic salt such as triethylamine, diisopropylethylamine or pyridine.

The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, usually at 130 to 40 ° C, preferably at 110 to 10 ° C. The reaction time varies mainly depending on the reaction temperature, the type of the reaction reagent, and the like, but is usually 30 minutes to 10 hours. Manufacturing method 3

Wherein R ² , R ³ , R ⁷ and R have the same meanings as described above, and R ⁸ is an alkane sulfonyl group such as methanesulfonyl, ethanesulfonyl, prono, 'n-sulfonyl or butanesulfonyl, phenylsulfonyl or It represents an arylsulfonyl group such as tolylsulfonyl, a dialkylphosphoryl group such as dimethylphosphoryl, dimethylphosphoryl, diisopropylphosphoryl or dibutylphosphoryl, or a diarylphosphoryl group such as diphenylphosphoryl or ditolylphosphoryl. ]

Compound (II) is a solvent that does not inhibit the reaction (eg, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetate) Compound (VI) described in JP-A-8-126676 or the like is dissolved in a medium, dimethyl sulfoxide or the like, or a mixture thereof, and is dissolved in an amount of about 1 to 5 times, preferably about 1 to 5 moles in the presence of a base. It is obtained by reacting with 1 to 3 times the molar amount of the mercapto compound (VII).

The base to be used is not particularly limited, but preferably includes an inorganic base such as sodium hydrogencarbonate and carbonated carbonate, or an organic base such as triethylamine, diisopropylethylamine, and pyridine.

The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at -30 to 40 ° C, preferably at -10 to 10 ° C. The reaction time varies depending mainly on the reaction temperature, the type of the reaction reagent, etc., but is usually 30 minutes to 10 hours.

Compound (VII), which is a starting material for synthesizing compound (II), is obtained as follows.

(IX) (X)

R ^{1 (J} removal

[Wherein, R ² , R ³ , R and Y have the same meanings as above, R ^a represents a protecting group for an amino group, and R ^lfl represents a protecting group for a thiol group. ]

Compound (VII) is obtained by removing R ⁹ which is an amino protecting group of compound (IX) of compound (IX) described in JP-A-60-233076 by a method known per se, and leading to compound (X). Is reacted with compound (V) in the same manner as in Production Method 2 to give compound (XI), and then the thiol-protecting group R ^{1 (1} is removed by a known method. As the protecting group for the thiol group and the amino group, a protecting group used in the art in this field can be used. Manufacturing method 4

[Wherein, R ² , R ³ , R ⁷ , R and Y are the same as defined above. Compound (II) can be obtained by reacting compound (VIII) described in JP-A-60-233076 with compound (V) in the same manner as in Production Method 2.

The carbane compound (I〗) thus obtained can be converted into a carboxylic acid derivative in which R ⁷ is a hydrogen atom by removing the carboxyl protecting group according to a conventional method, if necessary. Can be converted. The method for removing the protecting group varies depending on the type, but can be generally removed by a method known in the art. Manufacturing method 5

(VII)

[Wherein, R ¹ , R ² , R ³ , R ⁸ and R have the same meanings as described above. ]

Compound (I) is a solvent that does not inhibit the reaction (for example, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N, N-dimethylformamide, N, N —Dissolve Compound (XII) in dimethyl ether amide, dimethyl sulfoxide, etc., or a mixture thereof), and dissolve in the presence of a base in an amount of about 1 to 5 moles, preferably about 1 to 3 moles. It is obtained by reacting with a mercapto compound (VII).

The base used is not particularly limited, but is preferably an inorganic base such as sodium bicarbonate or carbonated carbonate, or triethylamine, or disopropylethylamine. And organic bases such as pyridine.

The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at 130 to 40 ° C, preferably at −10 to 10 ° C. The reaction time varies depending mainly on the reaction temperature, the type of the reaction reagent, etc., but is usually 30 minutes to 10 hours.

The ketorubenem compound (I) or the ketorubanem compound (II) is purified as necessary by a conventional method, for example, a recrystallization method, preparative thin-layer chromatography, or column chromatography. be able to. It can be purified as a salt if necessary.

Preferred configurations of compound (I) and compound (II) which are the objects of the present invention are the following compound (Ia) and compound (lib).

[Wherein, R ¹ , R ² , R ³ and R are as defined above. ]

[Wherein, R ² , R ³ , R ⁷ and R are as defined above, respectively. ]

Oral administration of the compound (I) is rapidly absorbed into the blood As a metabolite, the compound is a compound of formula (IV) in which R ¹ is a hydrogen atom, and has a high blood concentration.

Therefore, the prophylactic / therapeutic agent for infectious disease containing the carbane compound (I) has an excellent action as described above by oral administration, and is usually administered as an oral agent.

The infectious disease preventive / therapeutic agent can be produced by diluting with a pharmaceutical excipient according to a method known per se. Examples of the excipient include starch, lactose, sugar, calcium carbonate, calcium phosphate and the like.

For the prevention and treatment of the infectious disease, other additives may be added, if desired, such as a binder (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubrication Agents (eg, magnesium stearate, talc, etc.), and disintegrators (eg, carboquine methylcellulose, calcium, talc, etc.) are preferred additives. After mixing the various components, the mixture is formulated for oral administration according to a method known per se, for example, into a formulation suitable for oral administration such as capsules, tablets, fine granules, granular IJ, and dry syrup. Prevention and treatment of infectious diseases.

The dose of the compound (I) varies depending on the subject of administration, symptoms, etc. For example, when administered for adult purulent diseases, for example, a dose of about 1 to 4 O mg / kg Administer the body weight orally 1 to 4 times a day.

In addition, the potent compound (I) may be used as another antibacterial active substance, for example, an antibacterial agent (penicillins, aminoglycosides, cephapisporins, etc.) or a remedy for systemic symptoms caused by bacterial infection. (Antipyretic, analgesic, anti-inflammatory, etc.). Example

Next, the physical properties and production method of the compound of the present invention will be specifically described with reference to Examples, but the present invention is not limited by these.

Example 1

p-Nitrobenzyl (1 R, 5 S, 6 S) — 2— {(3 S. 5 S) [5— N, N-Dimethylaminocarbonyl-1-1 (5-methyl-12-oxo-1.3-dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-1-3-ylthio}-6-[(1R) — 1 —Hydroxityl] 1 1 1 Methylcarbapene 1 2—Em 1 3—Carboquinate

(2 S, 4 S) — 2— N, N—Dimethylaminocarbonyl 4- 4-mercapto

1- (5-Methyl-2-oxo-1, 3-dioxolen-41-yl) Methyloxycarbonylpyrrolidine (119 mg) is dissolved in acetonitrile (1 ml) and p-nitrobenzyl (1R. 5 S. 6 S) — 2-diphenylphosphoryl 1 6 — [(1 R) 1 1 — hydroxyethyl] — 1-methylcarbapen 1 — 2-em-1 3-carboxylate 1.15 g and diisopropyl 0.38 ml of ethylamine was added at 0 ° C. After stirring at the same temperature for 1 hour, 200 ml of ethyl acetate was added, washed with 100 ml of a saturated saline solution, and dried with anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 9

11 mg were obtained.

Ή-NMR (CD C 13 s δ pp): 1.27 (3 H, d), 1.33 (3 H, d), 1, 7-2.1, 2.5-2.9 ( 2 H, m), 2.17 (3 H, s), 2.8 to 4.4 (13 H, m), 4.6 to 5.6 (5 H, m), 7.6,

8.2 0 (4 H. Α ₂ 'B ₂ ').

Example 2

(1 R, 5 S, 6 S)-2-{(3 S, 5 S) — [5—N, N—dimethylaminocarbonyl-1- 1 — (5-Methyl-1-oxo- and 3-Doxolen-4-) Myloxycarbonyl] pyrrolidine—3-ylthio} -6-[(1) -1-hydroxitytyl] -1-methylcarbapene-2-emum-3-potassium sodium rubonate

p-Nitrobenzil (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5-N, N-dimethylaminocarbone 1,3-Dioxolene-4-yl) methyloxycarbonyl] pyrrolidine-1-ylthio } — 6— [(1 R) — 1-Hydroxityl] — 1-Methylcarbapene 1—2—Em 3—3-Rubixylate 33 Omg in 17 mL of tetrahydrofuran and 0.1 M MOPS buffer ( ρΗ 7.0) was dissolved in a 17 ml mixed solution, 10% palladium carbon 33 Omg was added, and the mixture was hydrogenated at room temperature for 16 hours. The reaction solution was subjected to celite filtration, and the obtained filtrate was washed with getyl ether and concentrated under reduced pressure to about 5 ml. The obtained solution was subjected to close chromatography using Diaion HP-21 (manufactured by Mitsubishi Kasei Kogyo), concentrated under reduced pressure, and lyophilized to obtain 13 Omg of the title compound.

IR (Nu jo 1.cm " ¹ ): 3 3 9 3, 1 8 1 9, 1 7 6 7, 1 7 0 7, 1 6

4 3

_{Ή-NMR (DMSO- d β,} (5 pm): 1. 1 6 (3 H, d), 1. 4~ 1. 9 (1 H, m), 2. 1 3 (3 H, s), 2.82 (3H, s), 3.01 (3H, brs). 4.5 to 5.0 (3H, m).

Example 3

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[

5 -N, N-Dimethylaminocarbonyl 1 — (5-Methyl-2-oxo

3-dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-1-ylthio} — 6 — [(1R) —1-hydrodoxetyl] 1-11-methylcarbapene 1—hem1 3-carboxylate

(1 R, 5 S, 6 S)-2-{(3 S, 5 S) — [5— N, N—dimethylaminocarbone 1— (5—Methyl-2-oxo-1, 3-Dioxolen-1 4 96-Omg) Methyloxycarbonyl] pyrrolidin-1-ylthio} 16-[(1R) 111-hydroxyxethyl] -1-methylcarbapene-2-emu 3-sodium carboxylate 96 Omg Was dissolved in N, N-dimethylformamide (6 ml) and cooled to 5 ° C. Add 70 mg of bivaloyloxymethyl chloride, stir at the same temperature for 1 hour and at 35'C for 12 hours, add ethyl acetate 150mI, and add 5% saline solution 100m The mixture was washed with l and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was removed. Purification by silica gel column chromatography 1 gave 35 O mg of the title compound. IR (Nujo 1, cm ^-1 ): 3404, 1821, 1780, 1715.16.51.

Ή-NMR (CD C 1 a, (5 ρ pm): 1.22 (9 Η, s), 1.26 (3 Η, d), 1.31 (3 Η, d). 6-2.1, 2.5-2.9 (2Η, m), 2.17 (3Ηs), 2.8-4.4 (14, m), 4.80 (1 Η, m), 4.72, 4.99 (2 Η. ΑΒ q, J = 13.2 8 ζ), 5.87, 5.9 2 (2 Η, A Β q, J = 5.5 Η).

Example 4

Bivaloyloquinemethyl (1 R. 5 S. 6 S) — 2 — {(3 S, 5 S)-[5 -Ν, Ν—dimethylaminocarbonyl-1 — (5 —methyl-2-oxo-1 , 3-Dioxolen-1 4-yl) methyloxycarbonyl] pyrrolidine-1 3-ylthio} — 6 — [(1R) 1-1-hydroxylxethyl] 1-1-Methylcarbapene-1 2-em-1 —Carboxylate

(1) (1 R, 5 S, 6 S)-2-[(3 S, 5 S) — 5 — Ν, Ν—dimethylaminocarbonylpyrrolidine-1 4 —ylthio] 1 6 — [(1R) 1 1 -Hydroquinethyl] 1- 1-Methylcarbapene 1- 2-Em- 3- 3-Sodium rubonate 5 3 0 11 12 is suspended in 2.3 ml of 1 ^, アミ -dimethylformamide and heated to 5 ° C. Cool. Add 819 mg of pivalyloxymethyl iodide, stir at the same temperature for 1 hour, add ethyl acetate 15 1I, wash with 100 ml of 5% saline, and dry. It was dried over sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give bivaloyloquinmethyl (1R, 5S, 6S)-2-[(3S, 5S)-5 -N, N-Dimethylaminocarbonylpyrrolidine-1-4-ylthio] -16-[(1R) -1-1-Hydroxyshetyl] -1-methylcarbapene-12-emu-3-carboxylate 470 mg was obtained. .

'H-NMR (CD C 1 3, 5 p pm):.... 1. 2 2 (9 H, s) 1. 2~1 4 (6 H, m) 1. 5~1 8, 2. 4 to 2.8 (2H.m), 2.98 (3 H.s), 3.02 (3H, s), 3.0 to 4.4 (8H, m), 5.81, 5.95 (2H, AB q, J = 5.5 Hz).

(2) The compound (497 mg) obtained in (1) was dissolved in methylene chloride (5 ml), and the mixture was cooled to 5 and 5 ml. (5-Methyl-2-oxo-1.3-dioxolen-41-yl) Add 21 mg of methylthioquine carbonyl chloride and 0.14 ml of triethylamine and stir at the same temperature for 30 minutes. Then, add 150 ml of ethyl acetate and add 5% saline

It was washed with 100 ml and dried over anhydrous sodium sulfate. The reduced ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography to obtain 14 Omg of the title compound.

Example 5

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5 -N, N-dimethylaminocarbonyl 1 — (5-methyl-2-oxo- 1,3-Dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-1-3-ylthio} -1 6 — [(1R) —1-Hydroquinethyl] 1-11-methylcarbapene-12-1em— 3—Carboquin plate

The compound 5000012 obtained in (1) of Example 4 was dissolved in 2.5 ml of N-dimethylformamide, and the solution was dissolved in (5-methyl-12-oxo1-1,3-dioxolen-4-yl). ) Add 297 mg of methyl p-ditrophenyl carbonate and 0.14 ml of triethylamine, stir at room temperature for 2 hours, add 150 ml of ethyl acetate, and add 10% citrate. The mixture was washed with 100 ml of a 5% aqueous sodium bicarbonate solution (100 ml) and saturated saline solution (100 ml), and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 35 Omg of the title compound. Example 6

1-cyclohexyloxycarbonyloxyshetyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S) — [5 -N, N-dimethylaminocarbonyl-1- 1 — (5— Methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidine-1-ylthio} -6-[(1R) —1-Hydroxitytyl] — 1-Methylcarbapene 2-Emm-3-enecarboxylate

1-cyclohexyloxycarboxyloxoshetyl (1R, 5S, 6S) -2-({3S, 5S)-[5-N] obtained by the same method as (1) in Example 4. , N—Dimethylaminocarbonyl] pyrrolidine-3-ylthio} 1-6 — [(1R) -11-hydroxyxethyl] -1-methylcarbapene-12-em-1-carboxylate 2.0 g Dissolve in methylene chloride (20 ml), add (5-methyl-12-oxo-1,1,3-dioxolen-41-yl) methyl carbonyl chloride (83 Omg) and triethylamine (0.5 ml). After stirring at room temperature for 2 hours, ethyl acetate

150 ml was added, washed with 100 ml of 5% saline, and dried with anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 68 Omg of the title compound.

I R (N u j 0 1, cm "'): 3 4 0 2,1 8 2 1, 1 7 5 9.1 7 1 3,1 6 4 7.

Ή-NMR (CD C 1 a, 0 pp m):] .0 to 2.1 (20 H.m), 2.

16 (3H, s), 2.96 (3H, s), 3.06, 3.09 (3H, s),

3.0 to 4.4 (7H, m), 4.5 to 5.2 (4H, m), 6.7 to 7.0 (1H, q).

Example 7

1-Ethoxycarbonylcarbonylschityl (1R, 5S, 6S) -2-({3S, 5S)-[5-N, N-dimethylaminocarbone-2 1- (5-methyl-1-2 — Oxo-1, 3-dioxolen 4-1yl) methyloxycarbonyl] pyrrolidin-3-ylthio} 1-6—C (1R) -1 1 —hydroxylchityl] — 1-methylcarba'pen-1 2—emu3 —Carboxylate

1-etokincarbonyloxyshethyl (1R, 5S.6S) obtained by the same method as (1) of Example 4—2 — {(3S, 5S) — [5-N.N— Dimethylaminocarbonyl] pyrrolidine-1-3-ylthio} 1-6 — [(1R) —1-Hydroxyshetyl] -1-methylcarbapene-1-heme-3-carboxylate 1.O g Was dissolved in 5 ml of N, N-dimethylformamide, and (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methyl p-nitrophenyl carbonate 6

After adding 0.6 mg and triethylamine (0.29 ml), the mixture was stirred at room temperature for 2 hours, ethyl acetate (150 ml) was added, washed with 5% saline (100 ml), and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 30 Omg of the title compound.

1 R (Νυ j 0 1, cm-R: 34 0 4, 1 8 2 0, 1 7 5 8, 1 7 1 4, 1 6

5 0.

^ -NMR (CDC 13, δ ρ pm): 1.22 (3Η, t), 1.27 (3Η, d), 1.32 (3Η, d), 1.51 ( 3Η, d), 1.6 to 2.0, 2.5 to 2.8 (2 2, m), 2.16 (3Η, s), 2.8 to 4.4 (15 5) , m), 4.5-5.2 (3Η, m), 6.7-7.0 (1Η, q).

Example 8

ρ-Nitrobenzil (1 R. 5 S, 6 S)-2-C (3 S, 5 S)-(5-N, N-dimethylaminocarbonyl 1-propionyloxymethyloxycarbonyl) Pyrrolidin-1-3-ylthio] -1 6-C (1R) —1—Hydroxityl] 1-1-Methylcarbapene-12-Emm-1-3-Carboxylate

(2S, 4S) -2-N, N-dimethylaminocarbonyl-14-mercapto-1 1-propionyloxymethyloxycarbonylpyrrolidine 662 mg was dissolved in acetate methylene 1 1 ml, and nitrogen gas flow was applied. Bottom, p-nitrobenzil (1 R, 5 S.

6 S) 1-2-diphenylphosphorol 6-C (1 R) 1-1-hydroxyxethyl]-1 -methylcarbapene 1-2-em-1-3-carboxylate 1.15 g and disodium 0.38 ml of propylethylamine was added at 0 ° C. After stirring at the same temperature for 1 hour, 200 ml of ethyl acetate was added, washed with 100 ml of a saturated saline solution, and dried with anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 876 mg of the title compound.

_{Ή-NMR (CDC 1 3,} 5 p pm): 1. 1 4 (3 H, t), 1. 2 7 (3 H, d), 1.33 (3 H, d), 1.7 to 2.1, 2.5 to 2.9 (3 H, m), 2.40 (2 H, q), 2 . 8~4. 4 (1 3 H , m). 4. 6~5. 8 (5 H, m), 7. 6 4. 8. 2 0 (4 H. A 2 'B 2').

Example 9

(1 R, 5 S, 6 S)-2-C (3 S, 5 S) — (5-N, N-dimethylaminocarbonyl 1-propionyloquinomethyloxycarbonyl) pyrrolidin-1-ylthio]ー 6— [(1 R) — 1 —Hydroxityl] 1-methylcarbene pen 2- 2-emuu 3-Sodium sodium carboxylate

p-Nitrobenzyl (1R, 5S, 6S) -2-C (3S.5S)-(5-N.N-dimethylaminocarbonyl-1-1-propionyloxymethyloquincarbonyl) pyro Resin-1-3-ylthio] 16-[(1R) -1-1-Hydroxyshetyl] 1-1-Methylcarbapene-2-Em-3-Carboxylate 330 mg of tetrahydrofuran 17m Dissolved in a mixture of 17 ml of 1 M phosphate buffer (pH 7.0), added 33 Omg of 10% palladium carbon, and added hydrogen at room temperature for 16 hours. The reaction solution was filtered through celite, and the obtained filtrate was washed with getyl ether and concentrated under reduced pressure to about 5 ml. The resulting solution was subjected to chromatography using Diaion HP-21 (manufactured by Mitsubishi Chemical Industry), concentrated under reduced pressure, and lyophilized to obtain 128 mg of the title compound.

Ή-NR (D SO- d «, <5 p pm): 1.10 (3H, t), 1.17 (3H, d), 1-17 (3Η, d), 1. 4-1.9, 2.5-2.7 (2Η, m), 2.35 (2Η, q), 2.83 (3Η, s), 3.02 (3Η, brs) , 4.6 to 4.8 (1Η, t), 5.5 to 5.7 (2 (, m).

Example 10

ρ-Nitrobenzyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5-N, N-dimethylaminocarbonyl— 1-isobutyryloxymethyloxyl) (Bonyl) pi σ lysine-1-3-ylthio] -16-[(1R) -1-Hydroxitytyl] 1-1-Methylcarbapene-12-em-13-carboxylate (2S, 4S) -2-N.N-dimethylaminocarbonyl-41-mercapto-11-isobutyryloxymethyloxycarbonylpyrrolidine was prepared in the same manner as in Example 8 to give the title compound. I got

'H-NMR (CDC 13, δ p pm): 1.17 (6H.d), 1.27 (3H, d), 1.33 (3H, d), 1.7 to 2.1, 2.5 to 2.9 (H, m), 2.8 to 4.4 (13H, m), 4.6 to 5.8 (5H, m), 7.64 , 8.20 (H, A ₂ 'B ₂ ').

Example 1 1

(1 R, 5 S, 6 S) — 2— ((3 S, 5 S) — (5-N, N-dimethylaminocarbonyl-1 -isobutyryloxymethyloquincarbonyl) pyrrolidine-1

3- (ylthio) -1-6-((1R) —1—hydroxyl) —1-methylcarbapene 2- 2-emu 3-sodium sodium rubonate

p-Nitrobenzyl (1 R, 5 S. 6 S)-2-C (3 S, 5 S)-(5-N, N-dimethylaminocarbone 1-isobutyryloxymethyloxycarbonyl) ) Pyrrolidine-1-ylthio]-6-C (1 R)-1-hydroxyxetyl) 1-1-methylcarbapene-2-emu 3-Carboquinate in the same manner as in Example 9. The compound was obtained.

^J H-NMR (DMSO-de, (5 ppm): 1.0 to 1.4 (12H), 1.

4-1.9, 2.5 to 2.7 (3 H, m), 2.83 (3 H, s), 3.0 2 (3 H, brs), 4.6 to 4.8 ( 1 H, t), 5.5 to 5.7 (2 H, m).

Pivaloloquinmethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(

5-N, N-Dimethylaminocarboxyl 1-propionyloxymethyloxycarbonyl) pyrrolidin-13-ylthio] -1 6-[(1R) —1-Hydroxethyl] -11-methylcarbapene 1 2—Arm 1 3—Carbokinlet

(1 R, 5 S, 6 S)-2-C (3 S. 5 S) — (5-N, N-dimethylaminocarbonyl-1 -propionyloquinomethyloxycarbonyl) pyrrolidine-1 3- (ylthio) -1 6- ((1R) -1 -Hydroxitytyl) 1 1-Methylcarbapene 1- 2-Emmou 3-carboxylate 9 13 mg dissolved in N, N-dimethylformamide 6 ml And cooled to 5 ° C. Add 700 mg of bivaloyloxymethyl iodide, stir at the same temperature for 1 hour and at 30 ° C for 1 hour, add ethyl acetate 15 Oml, and add 5% saline solution 100 ml And dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 33 Smg of the title compound.

IR (Nuj 0 1.cm " ¹ ): 34 4 5, 1 7 5 5, 1 72 4, 1 6 5 1.

-丽 R (CDC 13, 5 p pm): 1.1 (3 H, t), 1.22 (9 H, s), 1.26 (3H, d), 1.32 (3 H , d), 1.7 to 2.1, 2.4 to 2.8 (3H, m), 2.38 (2H, q), 2.96 (3H, d). 0 9 (3H, d), 3.0 to 4 (7H, m) .4.73 (1H, m), 5.6 to 5.8 (2H, m), 5.88 (2 H, AB q).

Example 13

Bivaloyloquinmethyl (1R, 5S, 6S) —2 — [(3S, 5S)-(5-1N, N-dimethylaminocarbocarbonyl 1—propionyloquinmethylquinoquin carbonyl) 1-pyrrolidine-3-ylthio] -1 6-[(1R) -1-hydroxyl]-1-methylcarbapene-2-am- 3-carboxylate

(1) (1 R, 5 S, 6 S)-2-C (3 S, 5 S) — 5— N, N-dimethylaminocarbonylcarbonylpyrrolidine-1-ylthio] 1 6— [(1 R) — 1-Hydroxyshethyl] 11-Methylcarbapene 12-Emm-3-Sodium 3-carboxylate 3 1.38 was suspended in 1 ^, N-dimethylformamide 1 48 ml and cooled to 5 ° C. . Add 37.2 g of bivaloyloxymethyl chloride, stir at the same temperature for 1 hour, and add 3.19 g of potassium carbonate and 11.2 g of bivaloyloxymethyl chloride. After stirring at the same temperature for 1 hour, ethyl acetate (1.050 ml) was added, and saturated aqueous sodium hydrogen carbonate was added.

The mixture was washed with 75 ml and 500 ml of 5% saline, and dried over anhydrous sodium sulfate.

Ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Purified, Bivaloyloxymethyl- (1R, 5S, 6S) -2-C (3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidine-1-ylthio] -6

[(1R) -1-1-Hydroxystyl] 1-methylcarbapene-12-em-3-carboxylate 14.2 g was obtained.

Ή-NMR (CD C 13, ά p pm): 1.22 (9H, s), 1.2 to 1.4 (6H, m), 1.5 to 1.8, 2.2.4 to 2.8 (2H, m), 2.98 (3H, s), 3.02 (3H, s) .3.0-4.4 (8H, m), 5.81 , 5.95 (2 H, AB q).

(2) 9.5 g of the compound obtained in (1) was dissolved in 50 ml of dichloromethane, and 3.42 g of propionyloxymethyl p-nitrophenylcarbabonate was added at 5 ° C. After stirring at the same temperature for 5 minutes, the mixture was stirred at room temperature for 5 hours. The reaction solution was purified by silica gel column chromatography to obtain 1.1 g of the title compound.

Example 14

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S) — (5 -N, N-dimethylaminocarboxy 1-acetyloxymethyloxyl (Bonyl) pyrrolidine-1-3-ylthio] 1-6 — [(1R) —1-Hydroxyshetyl] 1-1-Methylcarbapene-12-Em-1-3-carboxylate

600 mg of the compound obtained in (1) of Example 13 was dissolved in 3.5 ml of N, N-dimethylformamide, and acetyloxymethyl p-nitrophenyl carbonate was dissolved. Add 200 mg and 0.1 ml of triethylamine, stir at room temperature for 2 hours, then add 100 ml of ethyl acetate, 100 ml of 100% citric acid and 100 ml of 5% aqueous sodium bicarbonate.

The extract was washed with 100 ml and 100 ml of a saturated saline solution, and dried with anhydrous sodium sulfate. Ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography to obtain 31 Omg of the title compound.

1 R (N ujo 1, cm ^-1 ): 34 22, 1 76 0, 1 7 24, 1 64 7.

Ή-NMR (CDC 1 a, ρ ρ pm): 1.22 (9 Η, s), 1.27 (3

3. d) .1.3 3 (3 Η, d), 1.7 to 2.1, 2.5 to 2.9 (3 Η, m ), 2.11 (3H, s), 2.97 (3H.d), 3.08 (3H.d), 3 • 1 to 4.4 (7H.m), 4. 7 3 (1H, m), 5.6 to 5.8 (2H, m), 5.89 (2H, AB q).

Example 15

Bivaloyl dimethyl (1 R. 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-dimethylaminocarbone 1-isobutyrylloquinmethyloxy Carbonyl) pyrrolidine-1-3-ylthio] 1-6 — [(1R) —1-Hydroxyethyl] -1-methylcarbapene-2-heme-3-carboquinate

55 Omg of the compound obtained in (1) of Example 13 was dissolved in 3.5 ml of dichloromethane, and 210 mg of isobutyryloxymethyl P-dito-π-phenylcarbonyl carbonate was added thereto. After stirring for 2 hours, add ethyl acetate i 00 ml, wash with i 0% citric acid 100 ml, 5% sodium bicarbonate aqueous solution 100 ml and saturated saline solution 100 ml, water-free It was dried with sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 21 Omg of the title compound.

IR (Nu j 0 1, cm " ¹ ): 3 3 8 5, 1 7 9 6, 1 7 5 3, 1 7 3 0, 1 6 3 6.

'Η— NMR (CD C 13, 6 p pm): 1.15 (6 H, d), 1.22 (9 H, s), 1.26 (3 H, d), 1.3 3 (3H, d), 1.7 to 2.1.2.2.5 to 2.9 (H, m), 2.95 (3H, d), 3.09 (3H, d) , 3.1 to 4.4 (7H, m), 4.73 (1H, m), 5.6 to 5.8 (2H, m), 5.88 (2H, AB q).

Example 16

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-dimethylaminocarboxyl 1-Bivaloyloxymethyloquinone Luponyl ) Pyrrolidine-1-3-ylthio] 1-6-((1R)-1-Hydroxethyl)-1-Methylcarbapene-2-Emu 3-Carboquinate

The compound (58 Omg) obtained in Example 13 (1) was treated with dichloromethane (3.5 m 1). In water, add 200 mg of bivaloyloxymethyl ρ-nitrophenylcarbonate, stir at room temperature for 2 hours, add 10 mL of ethyl acetate, and add 5% aqueous sodium bicarbonate 10%.

The extract was washed with 0 ml and saturated saline 100 ml, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 30 Omg of the title compound.

1 R (Nu j 0 1, cm_R: 3 4 2 3, 1 7 7 7, 1 7 5 1, 1 7 2 6, 1 6 4 9.

Ή-NMR (CD C 13, δ ρτη) 1.22 (18 H, s), 1.26 (3 Η, d), 1.33 (3 Η, d), 17-2. 1, 2.5 to 2.9 (3H.m), 2.96 (3Η, s) 3.09 (3H, d), 3.1 to 4.4 (7H.m) , 4.73 (1Η, m) 5.6 to 5.8 (2H, m), 5.88 (2H, ΑΒq).

Example 17

Bivaloyloxymethyl (1 R. 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-dimethylaminocarboxyl 1-isovalerylloquinmethyloxycarbonyl ) Pyrrolidine-1-3-ylthio] 1-6 — [(1R) -1—Hydroxyethyl] —1—Methylcarba'pen-2-hem-3-3-carboxylate

The title compound was obtained in the same manner as in Example 16.

'HNR (CDC 13, δ ρ pm): 0.96 (6 Η, d) 1.2 2 (9 Η, s), 1.26 (3 Η, d), 1.3 3 (3 H, d), 1.5-2.9 (6

H, m), 2.97 (3 H, s), 3 09 (3 H, d), 3.1 to 4.4 (7 H, m), 4.73 (1 H, m) , 56-5.8 (2H, m) 5.87 (2H, AB q).

Example 18

Pivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -N, N-dimethylaminocarbone 1-t-butylacetyloxy) Methyloxycarbonyl) pyrrolidine-1-3-ylthio] -1 6 — [(1R) -1—hydro Quichetyl] 11-Methylcarbapene 12-emu 3-carboquinate The title compound was obtained in the same manner as in Example 16.

'H-NMR (CDC 13, δ ρ pm): 0.98 (9 Η, s) 1.22 (9 Η, s), 1.26 (3 Η.d), 1.33 ( 3 Η, d), 1.7—2.9 (5

Η, m), 296 (3 Η, s) 3 08 (3 Η, d), 3.Total 4.4 (7 Η, m), 473 (1 Η, m) 5 6 to 5. 8 (2Η, m) 5.87 (2Η, ΑΒq).

Example 19

1-cyclohexyloxycarbonyloquinethyl (1R, 5S, 6S) -2 — [(3S, 5S)-(5-N.N-dimethylaminocarbinyl 1-isobu Tyrylloquinmethyloxycarbonyl) pyrrolidine-1-3-ylthio] -1 6-[(1R) -11-hydroxyxethyl] 1-1-1-Methylcarbapene-12-em-13-Carboxylate

1-Cyclohexyloxycarbonyl niloquinethyl (1R, 5S, 6S) —2 — [(3S, 5S)-(5-N) obtained by a method similar to (1) in Example 13 N-Dimethylaminocarbonyl) pyrrolidine-3-ylthio] -1-6-C (1R) -1-hydroxyhexyl] -11-methylcarbapene-2-em-13-carboxylate 1.0 g Dissolved in 10 ml of dichloromethane, added with 50 mg of isobutyryloxymethyl p-ditrophenyl carbonate, stirred at room temperature for 2 hours, evaporated the solvent, and concentrated the residue by silica gel column chromatography. Purification gave 355 mg of the title compound.

Ή-NMR (CD C 1 a, <5 ppm): 1.0 to 2.1 (27 H.m), 2.96 (3 H, s) .3.06, 3.09 (3H, s) .3.0 to 4.4 (7H.m), 4.73 (1H, m), 5.6 to 5.8 (2H, m), 6.7 to 7 . 0 (

1 H, q).

Example 20

(1) 1-Ethkincarbonylcarbonyloxethyl (1 R, 5 S, 6 S) — 2— [(3 S , 5 S) — (5 -N, N-dimethylaminocarbonyl 1-pivaloyloxime tyloxycarbonyl) pyrrolidine—3-ylthio] 1 6— ((1 R) — 1—hydroxyl) 1-Methylcarbapene-2-em-3-carboxylate The title compound was obtained in the same manner as in Example 19.

'H—NMR (CDC 13.Dp pm): 1.22 (3H, t), 1.22 (9

H, s), 1.27 (3H, d), 1.32 (3H, d), 1.51 (3H, d), 1.6 to 2.0, 2.5 to 2 8 (2 H, m), 2.8 to 4.4 (15 H, m), 4.73 (1 H, m), 5.6 to 5.8 (2 H. m), 6 Ί ~ Ί · 0 (1 H, q).

Experimental example

Next, in order to clarify the excellent properties of the compound of the present invention, an oral absorption experiment was performed as follows.

Experimental example 1 (oral absorption experiment)

The compound of the present invention (the compound of Example 13) 1 O OmgZkg was orally administered to mice (3 mice per group), and 0.25, 0.5,

Each plasma concentration at 1.0, 2.0, and 3.0 hours was measured by the HP LC method _(the results are shown in Table 1).

table 1

Experimental example 2 (oral absorption experiment)

The compound of the present invention (compound of Example 15) 1 O OmgZkg was orally administered to mice (3 mice per group), and 0.25, 0.5, 1.1 of the hydrolyzed potato compound (A) was hydrolyzed. 0, 2.0, each plasma concentrations after 3.0 hours, shown in Table 2 _£ results measured by the HPLC method. Table 2

Industrial applicability

The compound of the present invention (I) has excellent gastrointestinal absorption by oral administration and exhibits sufficient antibacterial properties against a wide variety of bacterial species, and is useful for infections (particularly bacterial infections). It is extremely useful as a preventive and therapeutic agent. The therapeutic agent for preventing infectious diseases is used for diseases caused by bacteria in warm-blooded animals including humans (dogs, cats, cows, horses, rats, mice, etc.) (eg, purulent diseases, respiratory infections, biliary tract) Infections, urinary tract infections, etc.). In addition, the compound

(II) is useful as an intermediate compound of the carbane compound (I). This application is based on Japanese Patent Application No. 12210/1998 filed in Japan and Japanese Patent Application No. 200370/1998, the contents of which are incorporated herein by reference. All are included.

Claims

The scope of the claims

1. Single branch type (I)

[Wherein, R ¹ is a modifying group that is hydrolyzed in vivo, R ² and R ³ may be the same or different and each represents a lower alkyl group, and R is a group represented by the formula (B)

-CH ₅

Or a group represented by the formula (C)

(Wherein, R ⁴ and R ⁵ may be the same or different and each represents a hydrogen atom or a lower alkyl group, and R ⁶ represents an alkyl group having 1 to! 0 carbon atoms) A compound represented by the formula:

2. The compound according to claim 1, wherein R ² and R ³ may be the same or different and each is a low-alkyl group.

3. The compound according to claim ^{1, wherein} R ¹ is a bivaloyloquinmethyl group.

4. The compound according to claim 1, wherein R ¹ is a 1-cyclohexylquinocarbonylcarbonylquinethyl group.

5. The compound according to claim 1, wherein R ¹ is a 1-ethoxyquincarbonylquinethyl group.

6. Bivaloyloxymethyl (1 R, 5 S. 6 S)-2-{(3 S, 5 S)-[5 -N, N-dimethylaminocarbonyl— 1 — (5-methyl-2-oxo One one

, 3-Dioxolen-1-yl) methyloxycarbonyl] pyrrolidine-1-3-ylthio} 1-6 — [(1R) —1—Hydroxyethyl] —1-Methylcarbapene1-2—Em3 —Force ruboxylate,

1-cyclohexyloxycarbonyloxyshetyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5 -N, N-dimethylaminocarbonyl-1 i — Methyl 2-oxo-3 -dioxolene 41-yl) methyloxycarbonyl] pyrrolidine-13-ylthio} — 6 — [(1R) 1-1-Hydroxitytyl] 1-methylcarbapene One 2-Emu 3-Carboxylate,

1-Ethoxycarbonyloxyshethyl (1 R, 5 S. 6 S)-2-{(3 S, 5 S)-C 5 -N, N-dimethylaminocarbonyl — 1,2-dioxolene-4-yl) methyloxycarbonyl] pyrrolidin-1-3-ylthio} 1-6 — [(1R) -1] -hydroquininetyl] —Carboxylate,

Bivaloyloxymethyl (1 R, 5 S. 6 S)-2-C (3 S, 5 S) — (5 -N, N-dimethylaminocarbone 1-acetyloquinine methyloxycal (Bonyl) pyrrolidine-l-ylthio] -l6-((1R) -l-hydroxyl-yl) -l-methylcarbapene-l-em-l-3-carboxylate;

Viva α-yloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5 -Ν. Ν—Dimethylaminocarboyl 1 1-propionyloxymethyloquin carbonyl) Pyrrolidine 1 3- (ylthio) -1-6-((1R) -1-hydroxyethyl) -11-methylcarbene pen-2-hem-3-carboquinate,

Bivaloyloxymethyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S) — (5 -Ν, Ν—Dimethylaminocarbone 1 1-isobutylyloxyquinmethyloxy Carbonyl) pyrrolidine-1-3-ylthio] — 6—C (1R) -11-hydroquinethyl) 1 1 1-methylcarbapene 1-2-em-13-carboquinolate,

Bivaloyloquinmethyl (1 R, 5 S, 6 S)-2-C (3 S. 5 S)-(5 -N, N-dimethylaminocarbone 1 1-pipa'loyloquinmethyloxy Power rubonyl) pyrrolidine-l-ylthio]-6-C (1R)-1 -hydroquinethyl] -l-methylcarbapene -l -em -l -carboxylate,

Bivaloyloquinemethyl (1 R, 5 S. 6 S)-2-C (3 S, 5 S)-(5 -N, N-dimethylaminocarbonyl-2-methyl 1-isovaleryloxymethylmethyl) Carbonyl) pyrrolidine-3-ylthio] -1 6-[(1R) -11-hydroxyethyl] -11-methylcarbapene-12-amme-3-carboxylate,

Bivaloyloxymethyl (1 R, 5 S. 6 S)-2-C (3 S, 5 S) — (5—N, N—dimethylaminocarbocarbonyl 1-tert-butylacetyloxymethyl Oxycarbonyl) pyrrolidine-3-ylthio] -1-6-((1R) -1 -hydroxyxethyl) 1-1-methylcarbapene-2-em-13-carboxylate,

1 —Hexoxycarbonyloxyquinethyl (1 R, 5 S. 6 S)-2 — C (3 S, 5 S) 1 (5 -N, N—Dimethylaminocarbone 1 1 Ib tyrylloquinmethyloxycarbonyl) pyrrolidine-l-ylthio] -l6-((1R) -l-hydroxyethyl) -l-methylcarbapene-l- 2-em-l-carboxylate, and

1 —Ethokinecarbonyloxoshetyl (1 R, 5 S, 6 S)-2-C (3 S, 5 S)-(5-N, N—Dimethylaminocarbone 2 1 —Bivaloyloxime Tyloxycarbonyl) pyrrolidine-1-3-ylthio] -1 6-[(1R) -I-D-dixethyl] 1-1-Methylcarbapene-2-Emu3-Selected from the group consisting of carboxylates 2. The compound of claim 1.

7. An antibacterial agent comprising the active ingredient represented by the general formula (I) according to claim 1 as an active ingredient.

8. The antibacterial agent according to claim 7, which is for oral administration.

9. General formula (II)

[Wherein, R ² and R ³ may be the same or different and each represents a lower alkyl group, R ⁷ represents a hydrogen atom or a carboxyl protecting group, and R represents a group represented by the formula (B)

Or a group represented by the formula (C)

(Wherein, R ⁴ and R ⁵ may be the same or different, a lower alkyl group was or hydrogen atom, respectively, R ^e represents an alkyl group of 0 1 1 carbon atoms) a group represented by A compound represented by the formula: or a salt thereof.

1 0. p-Nitrobenzyl (1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5 -N. N-Dimethylaminocarbone 1 1 (5-Methyl-2 —Oxo-1.3-Dioxolen-1-41) methyloxycarbonyl] pyrrolidine-1-3-ylthio} 1 6 — [(1R) 1-1-hydroxyethyl] —1—methylcarbapene-1 2 1-mumu 3-carboxylate,

(1 R, 5 S, 6 S)-2-{(3 S, 5 S)-[5-N, N-dimethylaminocarbonyl-1- 1-(5 -methyl-2-oxo-3 -dioxolene 4- L) Methyloxycarbonyl] pyrrolidine-3-ylthio) -6-[(1R) -1-hydroxyxethyl] -11-methylcarbapene-12-em-1-3-carboxylic acid, p-nitrobe (1R, 5S, 6S) -2-C (3S, 5S)-(5-N, N-dimethylaminocarbonyl-2-yl-propionyloxymethyloxycarbonyl) pyrrolidine-1 —Ylthio) 1 6— C (1 R) 1 1-hydroxyxethyl) 1 1-methylcarbapene 1 2 — ham 1 3 —carboquinate,

p-Nitrobenzil (1 R, 5 S, 6 S) — 2— [(3 S, 5 S) -C 5 -N, N-dimethylaminocarbinyl 1 —isobutyryloxymethylo Xycarbonyl) pyrrolidine-1-3-ylthio] -1-6—C (1R) —1-hydroxylexetil] 1-11-methylcarbapene-1-2-emu-3-carboquinate,

(1 R, 5 S. 6 S) — 2— [(3 S, 5 S) _ (5—N, N—dimethylaminocarbonyl 1 — propionyloxymethyloxycarbonyl) pyrrolidine

3-ylthio] -1-6- (C (1R) -11-hydroxyxethyl) -11-methylcarbene pen-2-em-13-carboxylic acid, and

(1 R. 5 S, 6 S)-2-C (3 S, 5 S) — (5-N, N-dimethylaminocarbocarbonyl 1 —isobutyrylloquinmethyloxycarbonyl) pyrrolidine- 1 -ylthio] 1 6. The compound according to claim 9, wherein the compound is selected from the group consisting of 6-[(1R) -1—hydroxyethyl] -1-methylcarbapene-12-em-13-carboxylic acid or a salt thereof ( In particular, the sodium salt).